Postoperative Radiotherapy of Prostate Cancer: Adjuvant versus Early Salvage.

Results of three randomized clinical trials (RCTs) comparing adjuvant radiotherapy (ART) and early salvage radiotherapy (eSRT) of prostate carcinoma and a subsequent meta-analysis of the individual patient data from these RCTs were recently published. The results suggest that early eSRT is as effective and potentially less toxic than ART. Therefore, eSRT should be considered the standard of care. However, due to limitations in the RCTs, ART remains a valid treatment option in patients with the combination of high-risk features such as Gleason Score (GS) 8-10, positive surgical margins (R1) and pathological T-stage 3 or 4 (pT3/4). This article provides a critical appraisal of the RCTs and the rationale for recommendations adopted in the current national guidelines regarding patients with high-risk features after radical prostatectomy (RP): ART should be offered in case of pT3/pT4 and R1 and Gleason Score 8-10; ART can be offered in case of pT3/pT4 and R0 and Gleason Score 8-10 as well as in case of multifocal R1 (including pT2) and Gleason Score 8-10. In any case, the alternative treatment option of eSRT in case of rising PSA should be discussed with the patient

Rationale for Combining Radiotherapy and Immune Checkpoint Inhibition for Patients With Hypoxic Tumors

In order to compensate for the increased oxygen consumption in growing tumors, tumors need angiogenesis and vasculogenesis to increase the supply. Insufficiency in this process or in the microcirculation leads to hypoxic tumor areas with a significantly reduced pO2, which in turn leads to alterations in the biology of cancer cells as well as in the tumor microenvironment. Cancer cells develop more aggressive phenotypes, stem cell features and are more prone to metastasis formation and migration. In addition, intratumoral hypoxia confers therapy resistance, specifically radioresistance. Reactive oxygen species are crucial in fixing DNA breaks after ionizing radiation. Thus, hypoxic tumor cells show a two- to threefold increase in radioresistance. The microenvironment is enriched with chemokines (e.g., SDF-1) and growth factors (e.g., TGFβ) additionally reducing radiosensitivity. During recent years hypoxia has also been identified as a major factor for immune suppression in the tumor microenvironment. Hypoxic tumors show increased numbers of myeloid derived suppressor cells (MDSCs) as well as regulatory T cells (Tregs) and decreased infiltration and activation of cytotoxic T cells. The combination of radiotherapy with immune checkpoint inhibition is on the rise in the treatment of metastatic cancer patients, but is also tested in multiple curative treatment settings. There is a strong rationale for synergistic effects, such as increased T cell infiltration in irradiated tumors and mitigation of radiation-induced immunosuppressive mechanisms such as PD-L1 upregulation by immune checkpoint inhibition. Given the worse prognosis of patients with hypoxic tumors due to local therapy resistance but also increased rate of distant metastases and the strong immune suppression induced by hypoxia, we hypothesize that the subgroup of patients with hypoxic tumors might be of special interest for combining immune checkpoint inhibition with radiotherapy

Protocol of a phase II trial

Background Current studies on salvage radiotherapy (sRT) investigate timing, dose-escalation and anti-hormonal treatment (ADT) for recurrent prostate cancer. These approaches could either be limited by radiation-related susceptibility of the anastomosis or by suspected side-effects of long-term ADT. A phase II protocol was developed to investigate the benefit and tolerability of regional hyperthermia with moderately dose-escalated radiotherapy. Methods The study hypothesis is that radio-thermotherapy is a safe and feasible salvage treatment modality. The primary endpoint is safety measured by frequency of grade 3+ genitourinary (GU) and gastrointestinal (GI) adverse events (AE) according to Common Toxicity Criteria (CTC) version 4. Feasibility is defined by number of hyperthermia treatments (n ≥ 7) and feasibility of radiotherapy according to protocol. Target volume delineation is performed according to the EORTC guidelines. Radiation treatment is administered with single doses of 2 Gy 5×/week to a total dose of 70 Gy. Regional hyperthermia is given 2×/week to a total of 10 treatments. Results European centres participate in the phase II trial using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The initiating centres were participants of the SAKK 09/10 study, where the same patient criteria and target volume definition (mandatory successful performed dummy run) were applied insuring a high standardisation of the study procedures. Conclusions The introduced phase II study implements highly precise image-guided radiotherapy and regional hyperthermia. If the phase II study is found to be safe and feasible, a multicenter phase III study is planned to test whether the addition of regional hyperthermia to dose-intensified sRT improves biochemical control

Sarcoma classification by DNA methylation profiling in clinical everyday life: the Charité experience

Background: Sarcomas are a heterogeneous group of rare malignant tumors with more than 100 subtypes. Accurate diagnosis remains challenging due to a lack of characteristic molecular or histomorphological hallmarks. A DNA methylation-based tumor profiling classifier for sarcomas (known as sarcoma classifier) from the German Cancer Research Center (Deutsches Krebsforschungszentrum) is now employed in selected cases to guide tumor classification and treatment decisions at our institution. Data on the usage of the classifier in daily clinical routine are lacking. Methods: In this single-center experience, we describe the clinical course of five sarcoma cases undergoing thorough pathological and reference pathological examination as well as DNA methylation-based profiling and their impact on subsequent treatment decisions. We collected data on the clinical course, DNA methylation analysis, histopathology, radiological imaging, and next-generation sequencing. Results: Five clinical cases involving DNA methylation-based profiling in 2021 at our institution were included. All patients' DNA methylation profiles were successfully matched to a methylation profile cluster of the sarcoma classifier's dataset. In three patients, the classifier reassured diagnosis or aided in finding the correct diagnosis in light of contradictory data and differential diagnoses. In two patients with intracranial tumors, the classifier changed the diagnosis to a novel diagnostic tumor group. Conclusions: The sarcoma classifier is a valuable diagnostic tool that should be used after comprehensive clinical and histopathological evaluation. It may help to reassure the histopathological diagnosis or indicate the need for thorough reassessment in cases where it contradicts previous findings. However, certain limitations (non-classifiable cases, misclassifications, unclear degree of sample purity for analysis and others) currently preclude wide clinical application. The current sarcoma classifier is therefore not yet ready for a broad clinical routine. With further refinements, this promising tool may be implemented in daily clinical practice in selected cases

Local control and patient reported outcomes after online MR guided stereotactic body radiotherapy of liver metastases

IntroductionStereotactic body radiotherapy (SBRT) is used to treat liver metastases with the intention of ablation. High local control rates were shown. Magnetic resonance imaging guided radiotherapy (MRgRT) provides the opportunity of a marker-less liver SBRT treatment due to the high soft tissue contrast. We report herein on one of the largest cohorts of patients treated with online MRgRT of liver metastases focusing on oncological outcome, toxicity, patient reported outcome measures (PROMs), quality of life.Material and methodsPatients treated for liver metastases with online MR-guided SBRT at a 1,5 T MR-Linac (Unity, Elekta, Crawley, UK) between March 2019 and December 2021 were included in this prospective study. UK SABR guidelines were used for organs at risk constraints. Oncological endpoints such as survival parameters (overall survival, progression-free survival) and local control as well as patient reported acceptance and quality of life data (EORTC QLQ-C30 questionnaire) were assessed. For toxicity scoring the Common Toxicity Criteria Version 5 were used.ResultsA total of 51 patients with 74 metastases were treated with a median of five fractions. The median applied BED GTV D98 was 84,1 Gy. Median follow-up was 15 months. Local control of the irradiated liver metastasis after 12 months was 89,6%, local control of the liver was 40,3%. Overall survival (OS) after 12 months was 85.1%. Progression free survival (PFS) after 12 months was 22,4%. Local control of the irradiated liver lesion was 100% after three years when a BED ≥100 Gy was reached. The number of treated lesions did not impact local control neither of the treated or of the hepatic control. Patient acceptance of online MRgSBRT was high. There were no acute grade ≥ 3 toxicities. Quality of life data showed no significant difference comparing baseline and follow-up data.ConclusionOnline MR guided radiotherapy is a noninvasive, well-tolerated and effective treatment for liver metastases. Further prospective trials with the goal to define patients who actually benefit most from an online adaptive workflow are currently ongoing

Organ Preservation in Rectal Cancer: The Patients' Perspective

Organ preservation after a clinical complete response to radiochemotherapy is currently one of the most discussed topics in the management of rectal cancer. However, the patients' perspective has only been poorly studied so far. In this multicenter study, we examined 49 patients with locally advanced rectal cancer. The willingness to participate in an organ preservation study and the acceptance of the associated aspects such as intensified radiochemotherapy protocols, the need for close follow-up examinations and local regrowth rates were assessed. Attitudes were correlated with baseline quality of life parameters and psychological scales for “fear of progression”, “locus of control”, “depression”, and the “willingness to take risks”. A total of 83% of patients would consider the deferral of surgery in case of a clinical complete response (cCR). Three monthly follow-up studies and a 25% local regrowth rate are considered acceptable by 95% and 94% respectively. While 41% would be willing to exchange cure rates for a non-operative treatment strategy, a potentially more toxic radiochemotherapy in order to increase the probability of a cCR was the aspect with the lowest acceptance (55%). Psychological factors, in particular “locus of control” and “willingness to take risks”, influenced patient preferences regarding most of the assessed parameters. While in general a broad acceptance of an organ-preserving treatment can be expected, patient preferences and concerns regarding different aspects of this strategy vary widely and require specific consideration during shared decision making

Radiotherapy for hormone-sensitive prostate cancer with synchronous low burden of distant metastases.

PURPOSE The DEGRO Expert Commission on Prostate Cancer has revised the indication for radiation therapy of the primary prostate tumor in patients with synchronous distant metastases with low metastatic burden. METHODS The current literature in the PubMed database was reviewed regarding randomized evidence on radiotherapy of the primary prostate tumor with synchronous low metastatic burden. RESULTS In total, two randomized trials were identified. The larger study, the STAMPEDE trial, demonstrated an absolute survival benefit of 8% after 3 years for patients with low metastatic burden treated with standard of care (SOC) and additional radiotherapy (RT) (EQD2 ≤ 72 Gy) of the primary tumor. Differences in the smaller Horrad trial were not statistically significant, although risk reduction in the subgroup (< 5 bone metastases) was equal to STAMPEDE. The STOPCAP meta-analysis of both trials demonstrated the benefit of local radiotherapy for up to 4 bone lesions and an additional subanalysis of STAMPEDE also substantiated this finding in cases with M1a-only metastases. CONCLUSION Therefore, due to the survival benefit after 3 years, current practice is changing. New palliative SOC is radiotherapy of the primary tumor in synchronously metastasized prostate cancer with low metastatic burden (defined as ≤ 4 bone metastases, with or without distant nodes) or in case of distant nodes only detected by conventional imaging

Quantitative, Multi-institutional Evaluation of MR Thermometry Accuracy for Deep-Pelvic MR-Hyperthermia Systems Operating in Multi-vendor MR-systems Using a New Anthropomorphic Phantom

Clinical outcome of hyperthermia depends on the achieved target temperature, therefore target conformal heating is essential. Currently, invasive temperature probe measurements are the gold standard for temperature monitoring, however, they only provide limited sparse data. In contrast, magnetic resonance thermometry (MRT) provides unique capabilities to non-invasively measure the 3D-temperature. This study investigates MRT accuracy for MR-hyperthermia hybrid systems located at five European institutions while heating a centric or eccentric target in anthropomorphic phantoms with pelvic and spine structures. Scatter plots, root mean square error (RMSE) and Bland–Altman analysis were used to quantify accuracy of MRT compared to high resistance thermistor probe measurements. For all institutions, a linear relation between MRT and thermistor probes measurements was found with R2 (mean ± standard deviation) of 0.97 ± 0.03 and 0.97 ± 0.02, respectively for centric and eccentric heating targets. The RMSE was found to be 0.52 ± 0.31 °C and 0.30 ± 0.20 °C, respectively. The Bland-Altman evaluation showed a mean difference of 0.46 ± 0.20 °C and 0.13 ± 0.08 °C, respectively. This first multi-institutional evaluation of MR-hyperthermia hybrid systems indicates comparable device performance and good agreement between MRT and thermistor probes measurements. This forms the basis to standardize treatments in multi-institution studies of MR-guided hyperthermia and to elucidate thermal dose-effect relations

Statement from the DEGRO working group prostate cancer

Aim: To provide an overview on the available treatments to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer. Methods: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published and assessed the validity of the information on efficacy and treatment-related toxicity. Results: Eight randomized controlled trials and one meta-analysis were identified. Two randomized trials demonstrated that prophylactic radiation therapy (RT) using 1 × 10 Gy or 2 × 6 Gy significantly reduced the rate of gynecomastia but not breast pain, as compared to observation. A randomized dose-finding trial identified the daily dose of 20 mg tamoxifen (TMX) as the most effective prophylactic dose and another randomized trial described that daily TMX use was superior to weekly use. Another randomized trial showed that prophylactic daily TMX is more effective than TMX given at the onset of gynecomastia. Two other randomized trials described that TMX was clearly superior to anastrozole in reducing the risk for gynecomastia and/or breast pain. One comparative randomized trial between prophylactic RT using 1 × 12 Gy and TMX concluded that prophylactic TMX is more effective compared to prophylactic RT and furthermore that TMX appears to be more effective to treat gynecomastia and/or breast pain when symptoms are already present. A meta-analysis confirmed that both prophylactic RT and TMX can reduce the risk of gynecomastia and/or breast pain with TMX being more effective; however, the rate of side effects after TMX including dizziness and hot flushes might be higher than after RT and must be taken into account. Less is known regarding the comparative effectiveness of different radiation fractionation schedules and more modern RT techniques. Conclusions: Prophylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered